2. …Going to cover…..
Red blood cell disorders = Anemia and polycythemia
Bleeding disorders = platelets , vessels and clotting
White blood cell disorders = malignant
Disorders of the lymphoid tissues, thymus and
spleen
4. Learning objectives
1. Define anemia
2. Types of anemias, causes and pathophysiologic mechanisms
3. Clinical features and complications of anemia
4. Differentiating features/ diagnostic features
5. Correcting anemias
6. Define polycythemia, causes ,pathophysiologic mechanisms,
complications and diagnostic features
5. Outline
• Normal RBC development
• Anemias of - Blood Loss
- Diminished Erythropoiesis
- Hemolytic Anemias
• Polycythemia
6. Outline
• Normal RBC development
• Anemias of - Blood Loss
- Diminished Erythropoiesis
- Hemolytic Anemias
• Polycythemia
7. Tissues involved in hematopoiesis
Arbitrary classification…….
• Myeloid tissue- bone marrow and its derivatives(e.g.
erythrocytes , platelets ,granulocytes and monocytes)
• Lymphoid tissue-thymus , spleen and lymphnodes
8. Normal RBC Development
• Embryonic-Yolk sac mesenchyme- myeloid stem cells appear-
third week
• Fetal Liver-end of third month until shortly before birth
• 4thmonth stem cells migrate to bonemarrow spaces
9. Normal RBC Development
• Postnatal-active bone marrow in all bones, sole source
• By age 18-only vertebrae , flat bones, ends of humerus and
femur(Red marrow), rest yellow marrow (fat)
100 - Age= Marrow activity in %
18. Bone marrow morphology(aspirate or biopsy)
• Adult marrow- 1:1 fat cell to hematopoietic element
ratio(biopsy)
• Pluripotent and multipotent stem cells- 0.1% of the marrow
cells
19.
20. • 65% granulocytes and their precursors, 25% erythroid
precursors
• 10% lymphocytes and Monocytes and their precursors
• Myeloid to erythroid ratio= 2:1 -5:1
25. Outline
• Normal RBC development
• Anemias of - Blood Loss
- Diminished Erythropoiesis
- Hemolytic Anemias
• Polycythemia
26. Anemias
• A reduction below normal limits of the total circulating
red cell mass
• Measurements- reduced Hematocrit (volume of packed
red cell)
-reduced Hemoglobin concentration
27. Classification
• Based on- Underlying mechanism
- Alterations in red cell morphology…etiologic clues
can be found
28. Morphologic characteristics(qualitative RBC indices)
• Red cell size (normocytic , microcytic or macrocytic)
• Degree of hemoglobinization or color of red cells(
normochromic or hypochromic or 'hyperchromic‘ )
• Shape (ovalocytes , sickle cells, bite cells, helmet cells,…..)
(Variable size and shape= anisopoikilocytosis)
29.
30.
31.
32. Quantitative red cell indices
• Mean cell volume(MCV)- average volume of red blood cell(in
femtoliters or cubic micrometers)
• Mean cell hemoglobin(MCH) -average content(mass) of
hemoglobin per red blood cell (in picograms)
33. • Mean cell hemoglobin concentration(MCHC) -average
hemoglobin concentration in a given volume of packed red
cells(in grams per deciliter)
• RBC distribution width(RDW)- the coefficient of variation of
RBC volume
34. General clinical features
• Pallor of body parts , weakness, tinnitus, malaise and easy
fatigability….
• Dyspnea on mild exertion
• Cardiac failure , hepatic and renal failure
35. General clinical features
• Headache, dimness of vision , faintness, confusion,
restlessness ……
• Koilonychia - brittle, spooning of finger nails………..
36. Classification based on pathophysiologic mechanisms
1. Blood loss - Due to acute or chronic blood loss
2. Impaired or ineffective red cell production
3. Increase rate of destruction( hemolytic anemias)
37. Outline
• Normal RBC development
• Anemias of - Blood Loss
- Diminished Erythropoiesis
- Hemolytic Anemias
• Polycythemia
38. Anemias of Blood Loss
• Depends on the rate of hemorrhage, if external or internal
bleeding
• If massive bleeding- cardiovascular collapse
• If external can lead to iron deficiency anemia
39. Acute Blood Loss
• Initially hemodilution …reduced hematocrit
• Leukocytosis…release from the marginal pool
• Erythropoietin….marrow stimulation
40. Acute Blood Loss
• Appearance of reticulocytes(newly released RBCs)
• Striking increase in reticulocyte count to 10-15% after 7days
and throbmocytosis
41. Chronic Blood Loss
• Causes anemia when the rate of loss exceeds the
regenerative capacity of the marrow or iron reserves are
depleted
• Features of iron deficiency anemia
e.g. gastric ulcer, colonic cancer, abnormal uterine
bleeding.....
42. Outline
• Normal RBC development
• Anemias- Blood Loss
- Hemolytic Anemias
-- Diminished Erythropoiesis
• Polycythemia
44. Megaloblastic Anemias
• Two principal types
1.Pernicious anemia(major form of vit B12 deficiency anemia)
2. Folate deficiency anemia
45. Megaloblastic Anemias
- Common to all is impaired DNA synthesis and morphologic
features in the blood and marrow
- Erythroid precursors and red cells are large ‘’megaloblastic ’’
due to lack of maturation and division
- Vit. B12 and folic acid are co-enzymes for the synthesis of
thymidine
46. Megaloblastic Anemias
-However the synthesis of RNA and proteins is relatively
unaffected so cytoplasmic maturation proceeds in
advance of nuclear maturation….nuclear/cytoplasmic
asynchrony
51. Megaloblastic Anemias
Morphology
- Giant metamyelocytes and band forms
- Megakaryocytes …abnormally large and bizarre ,
multilobated nuclei
- Ineffective erythropoiesis…….mild to moderate iron over
load from absorption over several years
52.
53.
54. Megaloblastic Anemias
Anemias of vitamin B12 deficiency
Normal vit.B12 metabolism:
• Complex organometallic compound….cobalamin
• Present in meat, eggs, and dairy products
• Daily requirement 2-3mg, a balanced diet supplies for several
yrs
• Vit .B12 is absorbed by the intrinsic-factor dependent pathway
and an alternative mechanism
55.
56. Anemias of vitamin B12 deficiency
• Vitamin B12-IF complex is absorbed in the terminal ileum.
• Vitamin B12 binds to transcobalamin II and is secreted
into plasma.
– Delivered to metabolically active cells or stored in the
liver (6-9 years supply).
57. Anemias of vitamin B12 deficiency :
Etiology of Vit.B12 deficiency:
• Inadequate diet-reserve depletion/Malnutrition
• Achlorohydria and loss of pepsin(in some old people)
• Gastrectomy and pernicious anemia
58. Anemias of vitamin B12 deficiency
Etiology of Vit.B12 deficiency:
• Exocrine pancreas abnormality
• Ileal resection or diffuse ileal disease
• Tape worm…D.Latum…competing for nutrient
• High demand-Pregnancy, hyperthyroidism, disseminated
cancer and chronic infections
59. Anemias of vitamin B12 deficiency
Biochemical functions of Vit.B12 :
Two reactions need vit.B12
• Transmethylation reaction and isomerization of
methylmalonyl coenzyme A to succinyl coenzyme A
60.
61.
62. Anemias of vitamin B12 deficiency :
Biochemical functions of Vit.B12 :
• Lack of folate is the proximal cause of anemia in vit.B12
deficiency, as the anemia inevitably improves with
administration of folic acid
63. Anemias of vitamin B12 deficiency :
Biochemical functions of Vit.B12 :
• Interruption of the succinyl pathway and consequent
build-up of methylmalonate and propionate(a precursor)
could lead to the formation and incorporation of
abnormal fatty acids into neural lipids
64. Anemias of vitamin B12 deficiency :
Biochemical functions of Vit.B12 :
• Treatment with folate fails to improve neurologic deficits
in vit.B12 deficiency
65. Anemias of vitamin B12 deficiency : Pernicious anemia
• Is a specific form of megaloblastic anemia caused by
atrophic gastritis and an attendant failure of intrinsic
factor production that leads to vit.B12 deficiency
66. Anemias of vitamin B12 deficiency : Pernicious anemia
Incidence :
• All races
• ‘Disease of older age’- 5th to 8th decade of life
67. Anemias of vitamin B12 deficiency : Pernicious anemia
Pathogenesis :
• Possibly autoimmune , destruction of gastric
mucosa…chronic atrophic gastritis
• Patients with autoimmune disorders are predisposed to
develop antibodies against intrinsic factors
68. Anemias of vitamin B12 deficiency : Pernicious anemia
Morphology:
• Bone marrow and blood…see common features
69. Anemias of vitamin B12 deficiency : Pernicious anemia
Morphology:
Alimentary tract
• Tongue- shiny, glazed and ‘’beefy’’….atrophic glossitis
• Diffuse chronic gastritis, atrophy of fundic glands with
absence of parietal cells
• Intestinalization of the gastric mucosa with megaloblastic
changes….risk for adenocarcinoma
70. Anemias of vitamin B12 deficiency : Pernicious anemia
Morphology:
Central nervous system lesions:
• In 3/4ths of fulminant pernicious anemia
• Dorsal and lateral spinal tract myelin degeneration
…spastic paraparesis , sensory ataxia, severe paresthesias
in the lower limbs
71. Anemias of vitamin B12 deficiency : Pernicious anemia
Morphology:
Central nervous system lesions:
• Both motor and sensory pathways are involved….
‘subacute combined degeneration’ or ‘combined system
disease’
72. Anemias of vitamin B12 deficiency : Pernicious anemia
Clinical course:
Insidious in onset
Diagnostic features
1.Moderate to severe megaloblastic anemia
2.Leukopenia with hypersegmented granulocytes
3. Mild to moderate thrombocytopenia
73. Anemias of vitamin B12 deficiency : Pernicious anemia
Diagnostic features
4.Mild jaundice due to ineffective erythropoiesis and
peripheral hemolysis of red cells
5.Neurologic changes related to Posterolateral spinal tracts
74. Anemias of vitamin B12 deficiency : Pernicious anemia
Diagnostic features
6. Achlorohydria even after histamine stimulation
7. Inability to absorb an oral dose of cobalamin(assessed by
urinary excretion of radiolabeled
cyanocobalamin…shilling test )
75. Anemias of vitamin B12 deficiency : Pernicious anemia
Diagnostic features
8.Low serum levels of vit.B12
9. Elevated levels of homocysteine and methyl malonic acid
in the serum(more sensitive than serum vit.B12)
76. Anemias of vitamin B12 deficiency : Pernicious anemia
Diagnostic features
10. A striking reticulocyte response and improvement in
hematocrit levels beginning about 5days after parenteral
vit.B12
11. Serum antibodies to intrinsic factor are highly specific
for pernicious anemia
77. Anemias of vitamin B12 deficiency : Pernicious anemia
Clinical course:
-High level of homocysteine is risk for atherosclerosis and
thrombosis
- With Vit.B12 treatment anemia and neurologic
abnormalities can be corrected but gastric mucosal
changes are unaffected
78.
79. Megaloblastic Anemias
Anemias of Folate deficiency
-Caused by folic acid or more properly pteroylmonoglutamic
acid deficiency
-Neurologic changes don’t occur
80. Anemias of Folate deficiency
- Folic acid(more specifically FH4 derivatives)acts as an
intermediate in the transfer of one-carbon units such as
formyl and methyl groups to various compounds
81. Anemias of Folate deficiency
-Most dependent processes include
1. Purine synthesis
2. Conversion of homocysteine to methionine
3. Deoxythymidylate monophosphate synthesis
82.
83. Anemias of Folate deficiency
Etiology:
- Daily requirement 50-200mg
- Green vegetables- richest sources
- Lesser amounts in animal proteins(e.g. liver)
84. Anemias of Folate deficiency
Etiology:
- Boiling up to 5-10 minutes destroys the abundant folic
acid in raw foods
- Absorbed in the proximal jejunum
- Bodies reserve is modest and deficiency can arise within
months of negative balance
85. Anemias of Folate deficiency
Etiology:
- Three major causes
1. Decreased intake or absorption.. in alcoholics , elderly, GI
problems (Sprue , lymphoma), OCP, Pheyntoin
86. Anemias of Folate deficiency
Etiology:
- Three major causes
2. Increased requirements…pregnancy, infancy,
hematologic abnormalities e.g. hemolytic anemias,
disseminated cancer
87. Anemias of Folate deficiency
Etiology:
- Three major causes
3. Impaired use…drugs e.g. folic acid antagonists
metotrixate inhibit dehydrofolate reductase
88.
89. Anemias of Folate deficiency
Diagnosis:
- Reduced serum folate or RBCs
- Increased serum homocysteine
- Reticulocytosis after folate administration but difficult to
differentiate from a vit.B12 deficiency
90. Anemias of Folate deficiency
Diagnosis:
NB: Folate doesn’t prevent (and may even exacerbate) the
progression of the neurologic deficits typical of the vit.B12
deficiency states!
93. Outline
• Normal RBC development
• Anemias- Blood Loss
-Diminished Erythropoiesis
- Hemolytic Anemias
• Polycythemia
94. Iron deficiency anemia
• Most common nutritional disorder in the world
• High prevalence in developing countries
95. Iron deficiency anemia
Iron metabolism
• Iron balance is maintained largely by regulating the
absorption of dietary iron
• About 20% heme iron mostly in animal products(in contrast
to 1-2% Nonheme iron in vegetables) is absorbable
96. Iron deficiency anemia
Iron metabolism
• To maintain balance ~1mg of iron must be absorbed per day
• 10-15% of ingested iron is absorbed
• Daily requirement: 7-10mg for adult men and 7-20mg for
adult women
97. Iron deficiency anemia
Iron metabolism
• Total body iron content- ~2gm in women and up to 6gm in
men
• Functional and storage compartments
• 80% Functional in- hemoglobin , myoglobin , enzymes
• Storage(15-20%) – ferritin , hemosiderin
98. Iron deficiency anemia
Iron metabolism
• Healthy young females have substantially smaller stores than
do males
• Ferritin is a protein-iron complex found in all tissues
particularly in the liver , spleen, bone marrow and skeletal
muscle
99. Iron deficiency anemia
Iron metabolism
• In the liver most ferritin is stored in the parenchymal
cells(hepatocytes)
• Hepatocytic iron is from transferrin
100. Iron deficiency anemia
Iron metabolism
• Iron in the spleen and bone marrow is in the mononuclear
phagocytic cells derived from RBC degradation
• Small amounts of ferritin circulate in the plasma largely
derived from the storage pool of body iron
• Its level correlates well with body iron stores
101. Iron deficiency anemia
Iron metabolism
• Transferrin- iron transporting glycoprotein produced by the
liver
• Transports iron to erythroid cells
• 33% saturated with iron in normal individuals
• Most iron is absorbed in the duodenum(heme and Nonheme
iron via 2 mechanisms)
102.
103. Iron deficiency anemia
Iron metabolism
• Non-heme iron absorption in the diet is facilitated by ascorbic
acid, citric acid, sugar, amino acids and inhibited by
phosphates, tannates(as in tea)….
• An excellent candidate for negative ‘’iron metabolism
regulatory hormone’’ is Hepcidin
104. Iron deficiency anemia
Iron metabolism
• Hepcidin- a small liver derived plasma peptide which inhibit
iron uptake in the duodenum and iron release from
macrophages
• The concentration of Hepcidin falls as iron stores become
depleted
105. Iron deficiency anemia
Etiology:
1. Dietary lack … more in developing countries
• Infants- low iron in breast milk and cow’s milk iron has poor
bioavailability
• Impoverished, elderly…little meat due to limited income or
poor dentition
108. Iron deficiency anemia
Etiology:
4. Chronic blood loss
• Esp. external hemorrhage- peptic ulcer, hemorrhoid , gastric
carcinoma, colonic carcinoma, hook worm or pin worms
menorrhagia or uterine cancer
• Renal , pelvic and bladder tumors
109. Iron deficiency anemia
Morphology :
- Bone marrow mild to moderate erythroid hyperplasia
- Disappearance of stainable iron by Prussian blue stain
- Peripheral morphology- microcytic, hypochromic RBCs, pencil
cells(elongated red cells) is characteristic …..
110.
111.
112. Iron deficiency anemia
Clinical features :
- Common features and underlying conditions dominate e.g.
malnutrition, uterine abnormality
- Koilonychia, alopecia, atrophic tongue and gastric mucosa
and intestinal malabsorption….most due to deficient iron
dependent enzymes
113. Iron deficiency anemia
Clinical features :
- Plummer-Vinson syndrome- triad of
1. Microcytic hypochromic anemia
2. Atrophic glossitis
3. Esophageal webs
114. Iron deficiency anemia
Diagnosis:
- Depressed hemoglobin and hematocrit,
- Peripheral morphology(microcytic , hypochromic RBCs…)
- Low serum iron and ferritin
115. Iron deficiency anemia
Diagnosis:
- High total plasma iron binding capacity(transferrin
concentration) with resultant reduction of transferrin
saturation levels to below 15%
- Low hepcidin level
116. Iron deficiency anemia
Diagnosis:
‘’An alert clinician investigating unexplained
iron deficiency anemia will occasionally
discover an occult bleed or cancer and
thereby save life!’’
118. Learning objectives
1. Define anemia
2. Types of anemias, causes and pathophysiologic mechanisms
3. Clinical features and complications of anemia
4. Differentiating features/ diagnostic features
5. Correcting anemias
119. Anemia of Chronic Diseases
• Is common cause of anemia in hospitalized patients
• Is associated with reduced erythroid proliferation and
impaired iron utilization
• Can mimic iron deficiency anemia
120. Anemia of Chronic Diseases
• Three categories of illnesses
-Chronic microbial infections- Osteomyelitis , Tuberculosis,
bacterial endocarditis, and lung abscess…..
- Chronic immune disorders- rheumatoid arthritis and
regional enteritis……
-Neoplasms - Hodgkin lymphoma , carcinomas of the lung
and breast
121. Anemia of Chronic Diseases
Mechanisms:
• IL-1,TNF and INF-γ- impede the transfer of iron from the
storage pool to the erythroid precursors,
• suppress renal erythropoietin generation
• Stimulate hepcidin synthesis
122. Anemia of Chronic Diseases
Clinical features:
• Mild normocytic, normochromic or hypochromic microcytic
anemia
• Symptoms of the underlying diseases are prominent
123. Anemia of Chronic Diseases
Diagnosis:
• Increased storage iron in marrow macrophages, a high serum
ferritin level and a reduced total iron-binding capacity readily
rule out iron deficiency as a cause of anemia
• Treating the underlying condition and erythropoietin supply
corrects anemia
124. Aplastic Anemia
• A syndrome of marrow failure associated with
pancytopenia(anemia , neutropenia and thrombocytopenia)
• From suppression or disappearance of multipotent myeloid
stem cells
125. Aplastic Anemia
Etiology:
-Majority 65% ‘’Idiopathic’’
-Most cases of Aplastic anemia of ‘’known’’ etiology follow
exposure to chemicals and drugs
-Dose related- benzene, chloramphenicol, vincristine ….
- Idiosyncratic – chloramphenicol ,streptomycin, chlorpramazine,
phenylbutazone
126. Aplastic Anemia
Etiology:
-Whole body irradiation
- Viral infections e.g. hepatitis virus Non-A,Non-B,Non-C and
Non-G types, parvovirus B-19, EBV, HIV
- Fanconi anemia- rare autosomal dominant DNA repair defect
with associated congenital anomalies like absence of radius
and thumb
128. Aplastic Anemia
Pathogenesis:
-T-cells suppress the normal development of stem cells through
INF-γ and TNF production
-Evidenced by antithymocyte globulin response of anemia in 60-
70% of cases
129. Aplastic Anemia
Morphology:
-Bone marrow biopsy-largely fat with few plasma cells and
lymphocytes
-Marrow aspirate- ‘’dry tap’’
-Marrow aplasia is best appreciated in marrow biopsy
132. Aplastic Anemia
Clinical course :
- Can occur at any age or either sex
- Insidious onset
- Symptoms of anemia
- Petichiae and ecchymosis……from thrombocytopenia
- Persistent minor infections and sudden onset of chills, fever
and prostration…from granulocytopenia
133. Aplastic Anemia
Clinical course :
-Splenomegaly is characteristically absent, if present,
the diagnosis of Aplastic anemia should be seriously
questioned!
-Reticulocytopenia is the rule!
- RBCs can be normocytic, normochromic with slight
macrocytosis
134. Aplastic Anemia
Clinical course :
- Differentiate from aleukemic leukemia and Myelodysplastic
syndrome!
- The prognosis is unpredictable
- Withdrawal of toxins can lead to recovery in some cases
- Bone marrow transplantation…hope for cure
135. Pure Red Cell Aplasia
- Rare
- Marked hypoplasia of marrow erythroid in the setting of
normal granulopoiesis and thrombopoiesis
- Immune suppression of red cell production…mostly unknown
stimulus
136. Pure Red Cell Aplasia
- On occasion viruses (Parvovirus B19) and thymic
tumors(thymoma) and large granular lymphocytic leukemia ,
drug exposures
137. Pure Red Cell Aplasia
- No normoblasts except few proerythroblasts and
erythroblasts
- In few erythroblasts viral inclusion of parvovirus
- No reticulocytosis and macrocytic indices can be seen
138. Other forms of Marrow Failure
• Myelopthsic anemia …marrow Space-occupying lesions…
• All blood elements are affected and few erythroid and
myeloid progenitors appear in the peripheral
blood….leukoerythroblastosis
139. Other forms of Marrow Failure
• Mylopthsic anemia…..
• E.g. metastatic cancer- most common of breast , lung and
prostate origin
• Granulomatous inflammation , Myelofibrosis,
myeloproliferative disorders ….
140. Other forms of Marrow Failure
• Diffuse liver disease…different ways…marrow hypofunction
• Chronic renal failure….uremia…chronic hemolysis
…….reduced erythropoietin
production…dominant cause
142. Outline
• Normal RBC development
• Anemias - Blood Loss
- Diminished Erythropoiesis
- Hemolytic Anemias
• Polycythemia
143. Hemolytic Anemias
Share these features:
• A shortened red cell life span(N=120 days): i.e. premature
destruction of red cells
• Elevated erythropoietin levels and increased erythropoiesis in
the marrow and other sites
• Accumulation of products of hemoglobin catabolism
147. Extravascular hemolysis
• When red cells are rendered ‘foreign’ or become less
deformable
• Result in sequestration and phagocytosis
• ‘Work’ hyperplasia of the spleen and splenomegaly
149. Common morphologic features
• Increase in the number of
erythroid precursors(
normoblasts) in the marrow
• Extramedullary hematopoiesis in
the spleen, liver and lymphnodes
152. Classification based on pathogenetic mechanism in to:
• Intrinsic( intracorpuscular defect) and extrinsic(
extracorpuscular mechanism)
• In general, hereditary defects are due to intrinsic defects and
the acquired disorders to extrinsic factors such as
autoantibodies
153. Hemolytic Anemia due to Trauma to Red Cells
• Cardiac valve prosthesis
• Narrowing or obstruction of the microvasculature…
microangiopathic hemolytic anemia
• In malignant hypertension, SLE, TTP,HUS , DIC and
disseminated cancer
154. Hemolytic Anemia due to Trauma to Red Cells
Morphology
• Peripheral film- red cell fragments ( schistocytes), ‘’helmet
cells’’, ‘’burr cells’’, ‘’triangle cells’’…..
156. Hereditary Spherocytosis (HS)
• 3/4th autosomal dominant(AD), the rest autosomal recessive
and severe
• Its occurrence not well known in Ethiopia
• Caused by intrinsic defects in the red cell membrane that
render cells spheroid , less deformable, and vulnerable to
Splenic sequestration and destruction
157. Hereditary Spherocytosis (HS)
• Diverse mutations affecting RBC membrane stabilizing
proteins(ankyrin,spectrin,band3….)
• The most common cause of AD HS is mutation in red cell
ankyrin
158.
159. Hereditary Spherocytosis (HS)
• Reduced membrane stability leads to loss of membrane
fragments during exposure to shear stress in the circulation
• Loss of membrane relative to cytoplasm ‘forces’ the cell to
assume the smallest possible diameter for a given volume…..a
sphere
160.
161. Hereditary Spherocytosis (HS)
• In the life of the ‘’portly (overweight) ’’, inflexible spherocyte,
the spleen is the villain (evil)!
• Passing splenic cords for sherocytes is like ‘‘obese man
attempting to bend at the waist.’’
• Stagnation in the splenic cords predispose to hypoxia
associated osmotic injury and phagocytosis
163. Hereditary Spherocytosis (HS)
Morphologic features:
• Reticulocytosis, marrow hyperplasia , hemosiderosis and mild
jaundice
• Pigment stone in 50-70%, moderate splenomegaly(1/2-1kg)
• Spherocytosis is distinctive feature, but not pathognomonic
for HS e.g. Autoimmune hemolytic anemia
164. Hereditary Spherocytosis (HS)
Clinical features:
• Anemia, splenomegaly and jaundice at birth or late
• Aplastic crisis- in acute parvovirus infection (B19)
• Hemolytic crisis- intercurrent events e.g. infectious
mononucleosis
• Gall stones
165. Hereditary Spherocytosis (HS)
Diagnosis- family history, hematologic findings, lab data, and
osmotic lysis test in hypotonic salt solution
- Splenectomy is often beneficial
166. Hemolytic Anemia due to Red Cell Enzyme
Defects:Glucose-6-phosphate Dehydrogenase
Deficiency
167. Glucose-6-phosphate Dehydrogenase Deficiency
• X-linked recessive
• Leads to Inadequate reduced glutathione(GSH)
• Reduce the ability of red cells to protect themselves against
oxidative injuries,
169. Glucose-6-phosphate Dehydrogenase Deficiency
• Mature red cells(older) are more susceptible to free radical
damage
• G6PD associated hemolysis follows exposure to oxidant
stress( drugs, foods, and infections) e.g. antimalarials(
Chloroquine , premaquine)
172. Glucose-6-phosphate Dehydrogenase Deficiency
• Acute intravascular hemolysis usually begins 2-3 days
following exposure to the oxidants
• Most features of hemolytic anemias( e.g. splenomegaly,
cholelithiasis) are absent
174. Sickle Cell Disease
• A type of disease characterized by production of defective
hemoglobins
• Normal adult HbA(α2 β 2), small amounts of HbA2(α2 δ2) and
HbF(α2 γ2)
• Caused by point mutation in β globin chain with the resultant
HbS (sickled hemoglobin)
175. Sickle Cell Disease
• Heterozygotes 40% of Hb is HbS
• As many as 30% are heterozygous in malaria endemic Africa
• Protective effect against Pf.malaria
176. Sickle Cell Disease
Pathogenesis:
• When deoxygenated , HbS molecules undergo aggregation
and polymerization….assume a needle-like fibers….. ‘sickle’ or
‘holly-leaf’ shape
177. Sickle Cell Disease
Pathogenesis:
• The precipitation of HbS fibers also cause oxidant damage ,
not only in irreversibly sickled cells but also in normal
appearing cells
• Repeated episodes of deoxygenation render sickle cells
abnormally sticky
178. Sickle Cell Disease
Pathogenesis:
The rate and degree of sickling depends on:
1.The amount of HbS and its interaction with the other Hb
chains
- Heterozygotes- no sickling unless severe hypoxia
- Is said to have 'sickle cell traits'
- Fetal Hb(HbF) inhibits polymerization of HbS
179. Sickle Cell Disease
Pathogenesis:
The rate and degree of sickling depends on:
2. The rate of HbS polymerization depends on the hemoglobin
concentration per cell
180. Sickle Cell Disease
Pathogenesis:
The rate and degree of sickling depends on:
3. A decrease in PH reduces the oxygen affinity of hemoglobin
augmenting the tendency for sickling
181. Sickle Cell Disease
Pathogenesis:
The rate and degree of sickling depends on:
4.The length of time red cells are exposed to low oxygen tension
-sickling is confined to the microvascular beds where blood
flow is sluggish
-Inflammation augments sickling
182. Sickle Cell Disease
The clinical manifestations are due to:
- Chronic hemolysis and occlusion of small blood vessels
183. Sickle Cell Disease
Morphology
• Bone marrow hyperplasia…prominent cheekbones and x-ray
‘crew cut’ skull bone
• Extramedullary hematopoiesis
• Splenomegaly in children…congestion , thrombosis ,
Infarction and fibrosis…. ‘ autosplenectomy '
184. Sickle Cell Disease
Morphology
• Pigment gall stones
• All patients develop hyperbilirubinemia during periods of
active hemolysis
• Reticulocytosis and 10-15% sickled cells in the peripheral
blood
187. Sickle Cell Disease
Clinical features
- Increased risk of infection by encapsulated organisms
e.g. pneumococci and H.influenza
-Septicemia and meningitis- most common causes of
death in children with sickle cell anemia
188. Sickle Cell Disease
Clinical features
- Vaso-occlusive crisis ….pain crisis usually induced by infections,
dehydration and acidosis
189. Sickle Cell Disease
Clinical features
-Pain crisis in children may be difficult to differentiate from
osteomyelitis
- Hand-foot syndrome….. Dactylitis
- Acute chest syndrome
190. Sickle Cell Disease
Clinical features
- Sequestration crisis…rapid splenic enlargement and shock
- Aplastic crisis….acute infection of erythroid progenitors by
parvovirus B19
191. Sickle Cell Disease
Diagnosis:
- Clinical findings , peripheral morphology, sickling test by
oxygen consuming agents e.g. metabisulfite, hemoglobin
electrophoresis
192.
193.
194. Where are we?
- Discussing about hemolytic anemias of
intrinsic or genetic causes......
198. β- Thalassemias
• Diminished synthesis of structurally normal β-globin chains,
coupled with unimpaired synthesis of α chains
• β0- Thalassemia-total absence of β-chain in the homozygous
state
• β+-Thalassemia –reduced(but detectable) chain in the
homozygous state
199. β- Thalassemias
• Anemia by two mechanisms:
• Deficit in HbA- ‘’under-hemoglobinized’’, hypochromic ,
microcytic red cells
• Diminished survival of red cells due to precipitated free α-
chains causing membrane damage
200. β- Thalassemias
• Anemia by two mechanisms:
• 70-80% of normoblasts suffer this fate..ineffective
erythropoiesis
202. β- Thalassemias
Clinical syndromes:
• Depends on the severity of the anemia which depends on the
type of genetic defect(β0 or β+) and the gene
dosage(homozygous or heterozygous)
• Severe anemia in thalassemia major(β0/β0 or β+/β+)
203. β- Thalassemias
Clinical syndromes:
• Mild anemia in heterozygotes … thalassemia minor or trait
• Compensatory marrow erythroid hyperplasia usually lead to
marrow expansion and bone deformities(cheek bones…)
• Extramedullary hematopoiesis(spleen , liver, lymphnodes and
extralymphoid sites)
204. β- Thalassemias
Clinical syndromes:
• Cachexia due to nutrient overuse by the proliferating
erythroid cells
• Secondary hemochromatosis - another disastrous
complication of thalassemia & other ineffective
erythropoiesis(excessive absorption of iron)
• The clinical course is brief unless transfusions are given
205. β- Thalassemias
Clinical Syndromes:
• Thalassemia trait may offer resistance against Pf.malaria
• Bone erosion and new bone formation usually gives a ‘’crew-
cut’’ appearance on x-ray
206.
207.
208. α- Thalassemia
• Reduced or absent synthesis of α-globin chains
• Severity depends on the number of α-globins affected and
the effects of unpaired non-α chains
209. α- Thalassemia
Clinical syndromes
• Silent carrier state – single α-chain is affected
• α- thalassemia trait-deletion of 2 α-globin genes
• Hemoglobin H disease(β4) – deletion of 3 α-globin genes
• Hydrops fetalis - 4(all) α-globin genes are deleted, severe
anemia in the fetus, cardiac failure and edema
210. Reading Assignment:
- Immunohemolytic anemia & Paroxysmal nocturnal
hemoglobinuria (PNH)
- Prepare a short note from Robbins in not more than 15 lines for
the immune hemolytic anemia and in less than 10 lines for the
PNH.
NB: In hand writing, not in a print out!
213. Outline
• Normal RBC development
• Anemias- Blood Loss
- Hemolytic Anemias
- Diminished Erythropoiesis
• Polycythemia
214. Polycythemia
• Polycythemia or erythrocytosis
• Abnormally high concentration of red cells, usually with a
corresponding increase in hemoglobin level.
• Can be relative or absolute
215. • Relative - when there is hemoconcentration due to decreased
plasma volume e.g. Dehydration, excess use of diuretics
- Stress polycythemia or gaisbock syndrome-
hypertensive, obese and anxious ‘’stressed’’
216. • Absolute-when there is an increase in total red cell mass
• Absolute- Primary or secondary
• Primary: e.g. Polycythemia Vera....... Abnormal proliferation
of myeloid stem cells, normal or low erythropoietin levels
: Inherited activating mutations in the
erythropoietin receptor (rare)
217. • Absolute- Primary or secondary
• Secondary: Due to Increased erythropoietin levels
- Appropriate: lung disease, high-altitude living, cyanotic
heart disease
- Inappropriate: erythropoietin-secreting tumors (e.g.,
renal cell carcinoma, hepatoma, cerebellar
hemangioblastoma);
- Surreptitious erythropoietin use (e.g., in endurance
athletes)
